Despite successful therapeutic options for estrogen receptor-a (ERα)+ breast cancer, resistance to endocrine therapy frequently occurs leading to tumor recurrence. In addition to intrinsic changes in the cancer cells, herein we demonstrate that tumor cell-microenvironment interactions can drive recurrence at specific sites. By using two ERα+ cell lines derived from spontaneous mammary carcinomas in STAT1-/- mice (SSM2, SSM3), we establish that the bone microenvironment offers growth advantage over primary site or lung in the absence of ovarian hormones. While SSM3 did not engraft at primary and skeletal locations in the absence of estrogen, SSM2 selectively grew in bone of ovariectomized mice and following administration of aromatase inhibitors. However, SSM2 growth remained hormone-dependent at extraskeletal sites. Unexpectedly, bone-residing SSM2 cells retained ERα expression and JAK2/ STAT3 activation regardless of the hormonal status. These data position the bone microenvironment as a unique site for acquisition of tumor/estrogen independency and identify the first ERα+ hormone-independent tumor model in immunocompetent mice.

Original languageEnglish
Pages (from-to)49751-49764
Number of pages14
Issue number31
StatePublished - 2016


  • Bone
  • Breast cancer
  • Endocrine resistance
  • Hormone resistance
  • Skeletal metastasis


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